The following description is provided to assist the understanding of the reader. None of the information provided or references cited is admitted to be prior art to the present invention.
Lymphocytes are derived from pluripotent stem cells that originate in the fetal liver and bone marrow. T lymphocyte differentiation normally occurs via a series of discrete developmental stages involving an initial primitive progenitor cell without lymphocyte specific cell surface markers (CD34+CD3−CD4−CD8−), followed by acquisition of lymphocyte specific markers and loss of CD34 (CD34−CD3+CD4+CD8+), followed by differentiation into mature CD3+ T cells expressing either CD4 or CD8 (CD3+CD4+CD8− or CD3+CD4−CD8+). Hematopoietic stem cells that are self renewing and pluripotent constitute approximately 1% of low density nucleated bone marrow cells. These cells express a high level of CD34 antigen on their surface, and as these pluripotent cells develop and commit to either the lymphoid, monomyeloid or erythroid cell series, the level of CD34 decreases.
T and NK cells are key regulators in the defense against infections and malignancies and play a direct causative role in autoimmune diseases and graft-versus-host disease. T cells recognize antigenic determinants through a surface receptor called the T cell receptor (TCR). Although similar in function to surface bound immunoglobin, T cell receptors are not secreted. T cells mediate their prime immunological function through direct contact with infected host cells. These infected cells cooperate by displaying (presenting) antigenic fragments of foreign proteins on their surface as a means of signaling to T cells that they are infected. While T cells recognize antigens presented on all host cells, T cells are first activated to recognize these antigens by specialized antigen-presenting cells such as dendritic cells, B cells and macrophages. Antigen-presenting cells also express co-stimulatory molecules on their surfaces which are required for full T cell activation. Together with macrophages, T cells are the main component of the cell-mediated immune response and, through the release of soluble factors, are required for virtually all aspects of the immune response. In addition to the T cell receptor, T cells are characterized by two major T cell-specific surface markers, CD4 and CD8, which define functionally distinct T cell populations. CD4 T cells, called T helper cells, are activated through interaction with antigen-presenting cells and function primarily to activate CD8 T cells, also known as cytotoxic or killer T cells (CTL). CTLs are the main effector T cell mediating the destruction of infected host cells and only recognize foreign antigens that are bound to specialized molecules found on virtually all cells. Thus, most infected cells of the body may serve as CTL targets. Target cells are killed by factors released from CTLs that cause rapid target cell lysis or through the induction of a highly ordered program of events leading to cell death. In addition to activating CTLs, CD4 helper cells also regulate B cell activation through the release of soluble factors. Like B cells, most resting virgin T cells are short-lived unless activated to proliferate and generate both effector and memory T cells.
Natural killer cells do not require presentation of foreign or tumor-derived antigens on target cells to direct their cytotoxic action. NK cells possess a spontaneous cytotoxicity against a range of virally-infected and tumor cells that can be broadened following exposure to IL-2. Such cells are then called lymphokine-activated killer (LAK) cells. NK cells also bind antibody-coated cells and mediate a form of cell killing called antibody-dependent cell-mediated cytotoxicity. However, NK cytotoxicity is specifically inhibited by markers carried by most normal host cells. NK cells also produce a number of growth factors with wide ranging immunological and hematopoietic activity.
Mature T lymphocytes can be expanded and manipulated, and this strategy forms the basis of most current approaches to immunotherapy. In contrast, the developmental aspects of T and B lymphocyte populations have not fully been integrated into the design of immunotherapeutic interventions, due in part to the lack of robust culture models that support the differentiation of T and B cells from uncommitted stem and progenitor cells.